Included as part of the PRECAUTIONS section.
Effects On Serum Creatinine
TYBOST decreases estimated creatinine clearance due to
inhibition of tubular secretion of creatinine without affecting actual renal
glomerular function. This effect should be considered when interpreting changes
in estimated creatinine clearance in patients initiating TYBOST, particularly
in patients with medical conditions or receiving drugs needing monitoring with
estimated creatinine clearance.
Prior to initiating therapy with TYBOST, assess estimated
creatinine clearance [see DOSAGE AND ADMINISTRATION]. Dosage
recommendations are not available for drugs that require dosage adjustments in
TYBOST-treated patients with renal impairment [see ADVERSE REACTIONS, DRUG
INTERACTIONS, and CLINICAL PHARMACOLOGY]. Consider alternative
medications that do not require dosage adjustments in patients with renal
Although TYBOST may cause modest increases in serum
creatinine and modest declines in estimated creatinine clearance without
affecting renal glomerular function, patients who experience a confirmed
increase in serum creatinine of greater than 0.4 mg/dL from baseline should be
closely monitored for renal safety.
New Onset Or Worsening Renal Impairment When Used With Tenofovir
Renal impairment, including cases of acute renal failure
and Fanconi syndrome, has been reported when TYBOST was used in an
antiretroviral regimen that contained TDF.
- Coadministration of TYBOST and TDF is not recommended in
patients who have an estimated creatinine clearance below 70 mL/min because
dose adjustment of TDF is required below 50 mL/min and such dose adjustments
have not been established for coadministration with TYBOST [see DOSAGE AND
- Document urine glucose and urine protein at baseline [see
DOSAGE AND ADMINISTRATION] and perform routine monitoring of estimated
creatinine clearance, urine glucose, and urine protein during treatment when
TYBOST is used with TDF. Measure serum phosphorus in patients with or at risk
for renal impairment when used with TDF.
- Coadministration of TYBOST and TDF in combination with
concomitant or recent use of a nephrotoxic agent is not recommended.
In a clinical trial of TYBOST over 144 weeks (N=692), 10
(2.9%) subjects treated with TYBOST coadministered with atazanavir and TRUVADA®
and 11 (3.2%) subjects treated with ritonavir coadministered with atazanavir
and TRUVADA discontinued study drug due to a renal adverse event. Seven of the
10 subjects (2.0% overall) in the TYBOST group had laboratory findings
consistent with proximal renal tubulopathy leading to study drug
discontinuation compared to 7 of 11 subjects (2.0% overall) in the ritonavir
group. One subject in the TYBOST group had renal impairment at baseline (i.e.,
estimated creatinine clearance less than 70 mL/min). The laboratory findings in
these 7 subjects with evidence of proximal tubulopathy improved but did not
completely resolve in all subjects upon discontinuation of TYBOST
coadministered with atazanavir and TRUVADA. Renal replacement therapy was not
required in any subject.
Risk Of Serious Adverse Reactions Or Loss Of Virologic
Response Due To Drug Interactions
Initiation of TYBOST, a CYP3A inhibitor, in patients
receiving medications metabolized by CYP3A, or initiation of medications
metabolized by CYP3A in patients already receiving TYBOST may increase plasma
concentrations of medications metabolized by CYP3A. Initiation of medications
that inhibit or induce CYP3A may respectively increase or decrease
concentrations of TYBOST with atazanavir or darunavir.
Increased concentrations may lead to:
- clinically significant adverse reactions, potentially
leading to severe, lifethreatening, or fatal events from higher exposures of
- clinically significant adverse reactions from higher
exposures of TYBOST and atazanavir or darunavir.
Decreased antiretroviral concentrations may lead to:
- loss of therapeutic effect of TYBOST with atazanavir or
darunavir and possible development of resistance.
See Table 5 for steps to prevent or manage these possible
and known significant drug interactions, including dosing recommendations [see
DRUG INTERACTIONS]. Consider the potential for drug interactions prior to
and during TYBOST with atazanavir or darunavir therapy; review concomitant
medications during TYBOST with atazanavir or darunavir therapy; and monitor for
the adverse reactions associated with concomitant medications [see
CONTRAINDICATIONS and DRUG INTERACTIONS].
TYBOST or ritonavir when administered with either
atazanavir or darunavir may result in different drug interactions when used
with concomitant medications. Complex or unknown mechanisms of drug
interactions preclude extrapolation of ritonavir drug interactions to certain
TYBOST interactions [see DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].
Antiretrovirals That Are Not Recommended In Combination With
The following antiretrovirals are not recommended in
combination with TYBOST because dosing recommendations for such combinations
have not been established and coadministration may result in decreased plasma
concentrations of the antiretroviral agents, leading to loss of therapeutic
effect and development of resistance:
- More than one antiretroviral that requires
pharmacokinetic enhancement (i.e., two protease inhibitors or a protease
inhibitor in combination with elvitegravir)
- Darunavir in combination with efavirenz, nevirapine, or
- Atazanavir in combination with etravirine
- Atazanavir in combination with efavirenz in
- Darunavir 600 mg twice daily
- Other HIV-1 protease inhibitors including fosamprenavir,
saquinavir, or tipranavir
TYBOST in combination with fixed-dose combination tablets
that contain cobicistat is not recommended.
TYBOST in combination with lopinavir/ritonavir or
regimens containing ritonavir is not recommended due to similar effects of
TYBOST and ritonavir on CYP3A.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION).
Inform patients that TYBOST coadministered with atazanavir
or darunavir may interact with many drugs with potential serious implications
and that some drugs are contraindicated with TYBOST coadministered with
atazanavir or darunavir. Advise patients to report to their healthcare provider
the use of any other prescription or nonprescription medication, including
acid-modifying medications or herbal products, including St. John's wort [see CONTRAINDICATIONS,
WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
New Onset Or Worsening Renal Impairment
Inform patients that renal impairment, including cases of
acute renal failure and Fanconi syndrome, has been reported when TYBOST is used
in combination with a TDF containing regimen [see WARNINGS AND PRECAUTIONS].
Advise patients that TYBOST is not recommended during
pregnancy and to alert their healthcare provider if they get pregnant while
taking TYBOST [see Use In Specific Populations].
Inform patients that there is a pregnancy exposure
registry that monitors fetal outcomes in pregnant individuals exposed to TYBOST
during pregnancy [see Use In Specific Populations].
Instruct mothers with HIV-1 infection not to breastfeed
because HIV-1 can be passed to the baby in breast milk [see Use In Specific
Inform patients that TYBOST must be taken at the same
time as atazanavir or darunavir and with food once daily as prescribed. It is
important to take TYBOST and atazanavir or darunavir together on a regular
dosing schedule and to avoid missing doses. Counsel patients about the risks of
developing resistance to their HIV-1 medications.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a long-term carcinogenicity study in mice, no
drug-related increases in tumor incidence were observed at doses up to 50 and
100 mg/kg/day (males and females, respectively). Cobicistat exposures at these
doses were approximately 7 (male) and 16 (females) times, respectively, the
human systemic exposure at the therapeutic daily dose. In a long-term
carcinogenicity study of cobicistat in rats, an increased incidence of follicular
cell adenomas and/or carcinomas in the thyroid gland was observed at doses of
25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular
cell findings are considered to be rat-specific, secondary to hepatic
microsomal enzyme induction and thyroid hormone imbalance, and are not relevant
for humans. At the highest doses tested in the rat carcinogenicity study,
systemic exposures were approximately 2 times the human systemic exposure at
the therapeutic daily dose.
Cobicistat was not genotoxic in the reverse mutation
bacterial test (Ames test), mouse lymphoma, or rat micronucleus assays.
Impairment Of Fertility
Cobicistat did not affect fertility in male or female
rats at daily exposures (AUC) approximately 3-fold higher than human exposures
at the recommended 150 mg daily dose.
Fertility was normal in the offspring of rats exposed
daily from before birth (in utero) through sexual maturity at daily exposures
(AUC) of approximately similar human exposures at the recommended 150 mg daily
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
fetal outcomes in individuals exposed to TYBOST during pregnancy. Healthcare
providers are encouraged to register patients by calling the Antiretroviral
Pregnancy Registry (APR) 1-800-258-4263.
TYBOST coadministered with darunavir or atazanavir is not
recommended during pregnancy [see DOSAGE AND ADMINISTRATION]. In a
clinical trial of individuals taking cobicistat coadministered with darunavir,
exposures of cobicistat and darunavir were substantially lower during pregnancy
[see Data and CLINICAL PHARMACOLOGY].
TYBOST use during pregnancy has been evaluated in a
limited number of individuals as reported by the APR, and available data show
no difference in the rate of overall birth defects for cobicistat compared with
the background rate for major defects of 2.7% in a U.S. reference population of
the Metropolitan Atlanta Congenital Defects Program Â (MACDP) (see Data).
The rate of miscarriage is not reported in the APR. The estimated background
rate of miscarriage in clinically recognized pregnancies in the U.S. general population
In animal reproduction studies in rats and rabbits, no
evidence of fetal harm was observed with oral administration of cobicistat
during organogenesis at doses that produced exposures up to 1.4 and 3.3 times,
respectively, the maximal recommended human dose (MRHD) of 150 mg (see Data).
Because TYBOST is coadministered with atazanavir or darunavir and other
antiretroviral drugs, also refer to the prescribing information of each drug
for information about pregnancy.
Cobicistat coadministered with darunavir as a fixed dose
combination, in combination with a background regimen, was evaluated in a
clinical trial of 7 pregnant individuals taking darunavir/cobicistat prior to
enrollment and who were willing to remain on darunavir/cobicistat throughout
the study. The study period included the second and third trimesters, and
through 12 weeks postpartum. Six pregnant individuals completed the trial.
Exposure to darunavir and cobicistat as part of an
antiretroviral regimen was substantially lower during the second and third
trimesters of pregnancy compared with postpartum [see CLINICAL PHARMACOLOGY].
One out of 6 individuals who completed the study
experienced virologic failure with HIV- 1 RNA >1,000 copies/mL from the
third trimester visit through the postpartum period. Five individuals had
sustained virologic response (HIV-1 RNA <50 copies/mL) throughout the study
period. There are no clinical data on the virologic response when darunavir/cobicistat
is initiated during pregnancy.
There were no new clinically relevant safety findings
compared with the known safety profile of darunavir/cobicistat in
The APR has received prospective reports of live births
following exposure to cobicistatcontaining regimens during pregnancy, including
204 exposures in the first trimester and 58 exposures in the second/third
trimester. Birth defects occurred in 5 of 204 (2.5%, 95% CI: 0.8% to 5.6%) live
births with first trimester exposure of cobicistat-containing regimens.
Insufficient numbers of pregnancies with earliest exposure to cobicistat in the
second/third trimesters have been reported to the APR to estimate the rate of
birth defects in this population. Among pregnant mothers in the U.S. reference
population, the background rate of birth defects is 2.7%. There was no
association between cobicistat and overall birth defects observed in the APR.
Prospective reports from the APR of overall major birth defects in pregnancies
exposed to cobicistat are compared with a U.S. background major birth defect
rate. Methodological limitations of the APR include the use of MACDP as the
external comparator group. Limitations of using an external comparator include
differences in methodology and populations, as well as confounding due to the
Cobicistat was administered orally to pregnant rats at
doses of 0, 25, 50, and 125 mg/kg/day on gestation day 6 to 17. Maternal
toxicity (adverse clinical signs, decreased body weight and food consumption)
was noted at 125 mg/kg/day and was associated with increases in
postimplantation loss and decreased fetal weights. No malformations were noted
at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in
pregnant females was 1.4-fold higher than the exposures at the MRHD.
In pregnant rabbits, cobicistat was administered orally
at doses of 0, 20, 50, and 100 mg/kg/day during the gestation days 7 to 20. No
maternal or embryo/fetal effects were noted at the highest dose of 100
mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3-fold higher than
exposures at the MRHD.
In a pre- and postnatal developmental study, cobicistat
was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation day
6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat,
neither maternal nor developmental toxicity was noted. Systemic exposures (AUC)
at this dose were slightly lower than (0.9-fold) the MRHD.
There is no information regarding the presence of
cobicistat in human milk, the effects on the breastfed infant, or the effects
on milk production. The Centers for Disease Control and Prevention recommend
that HIV-infected mothers not breastfeed their infants to avoid risking
postnatal transmission of HIV.
Females And Males Of Reproductive Potential
TYBOST interacts with certain oral contraceptives [see
Safety and effectiveness of TYBOST in pediatric patients
younger than 18 years of age have not been established.
Clinical trials of TYBOST did not include sufficient
numbers of subjects aged 65 and older to determine whether they respond
differently from younger subjects.
No dosage adjustment of TYBOST is required in patients
with renal impairment, including those with severe renal impairment. No
clinically relevant differences in cobicistat pharmacokinetics were observed
between subjects with severe renal impairment and healthy subjects. TYBOST is
coadministered with atazanavir or darunavir; therefore, refer to the
prescribing information for atazanavir or darunavir for information regarding
dosing recommendations of these drugs in patients with renal impairment [see
TYBOST has been shown to decrease estimated creatinine
clearance without affecting actual renal glomerular function. Dosing
recommendations are not available for drugs that require dosing adjustment for
renal impairment when used in combination with TYBOST [see DOSAGE AND
ADMINISTRATION, WARNINGS AND PRECAUTIONS, ADVERSE
REACTIONS, and CLINICAL PHARMACOLOGY].
No dosing adjustment of TYBOST is necessary for patients
with mild-to-moderate hepatic impairment. No data are available in patients
with severe hepatic impairment. TYBOST is coadministered with atazanavir or
darunavir and other antiretroviral drugs; therefore, refer to the prescribing
information of these other drugs for information regarding dosing
recommendations in patients with hepatic impairment [see CLINICAL PHARMACOLOGY].